Project 2: Bacterial Determinants of Susceptibility Abstract: The outcome of tuberculosis infection varies tremendously between individuals; most people show no signs of disease but some people will develop progressive disease. These differences in outcome seem to arise both because of differences between people but also because of differences between the strains of Mycobacterium tuberculosis with which they are infected. Indeed, human genetic differences seem to interact with bacterial differences such that the same bacterium may be able to cause disease in one host but not another and similarly, one person may be susceptible to a given bacterium but not another. In this project, we seek to understand this intersection of bacterial features with host genetics, which we term ?host-pathogen preference?. In Aim 1, we will define the bacterial factors that influence host-pathogen preference by testing the growth of a very large number of M. tuberculosis strains in a panel of mice bred to be highly diverse (the CC mice). We will identify bacterial and host genetic markers for interactions that are very likely to cause disease and will test the ability of these markers to predict human disease. Aim 2, we will determine the mechanisms by which some bacterial strains are more virulent than others. Finally, in Aim 3, we will test the hypothesis that BCG vaccination protects against infection with some M. tuberculosis strains but not others. These studies will also allow us to develop experimental models of M. tuberculosis infection that reflect the diversity of bacteria that humans face and provide an avenue for more successful vaccine and therapeutic testing.